Programmed cell death 4 (PDCD4), a tumor suppressor gene, is involved in multiple biological processes such as cell apoptosis, transformation, invasion, and tumor progression [1,4]. It inhibits protein translation to suppress tumor development by binding to translation initiation factor eIF4A via its MA-3 domains or directly binding to 5' mRNA internal ribosome entry sites with an RNA binding domain [2]. PDCD4 also participates in various signal transduction pathways, and its expression is regulated by numerous factors like non-coding RNAs, proteasomes, estrogen, natural compounds, and inflammation [2].

In cancer research, PDCD4 has been found to be a potential substrate of DTL. DTL overexpression decreases PDCD4 protein levels through ubiquitination, enhancing cancer cell motility and proliferation [1]. In breast cancer, its decreased expression is associated with drug resistance and short overall survival, making it a potential prognostic marker [2]. In colorectal cancer, PDCD4 may serve as an independent prognostic factor and potential diagnostic tool [4]. In non-alcoholic steatohepatitis (NASH), PDCD4-deficient hepatocytes in mice show elevated MHCII expression due to CIITA activation, exacerbating NASH progression, indicating PDCD4's protective role in liver health [3]. In premature ovarian insufficiency (POI), PDCD4 expression is increased in affected ovarian granulosa cells, and PDCD4 knockout in mice improves POI-related parameters, involving the PI3K-AKT-Bcl2/Bax signalling pathway [5]. In atrial fibrillation, PDCD4 in mouse atrial myocytes promotes inflammation and fibrosis by activating the PPAR-γ/NF-κB pathway, contributing to structural remodeling [6].

In conclusion, PDCD4 is a multifunctional gene playing a crucial role in tumor suppression, cell-specific functions, and disease progression. Gene knockout models in mice have been instrumental in revealing its role in diseases such as cancer, NASH, POI, and atrial fibrillation, providing valuable insights into disease mechanisms and potential therapeutic targets.

References:

1. Cui, Haoran, Wang, Qin, Lei, Zhenchuan, Wang, Yunshan, Wei, Guangwei. 2019. DTL promotes cancer progression by PDCD4 ubiquitin-dependent degradation. In Journal of experimental & clinical cancer research : CR, 38, 350. doi:10.1186/s13046-019-1358-x. https://pubmed.ncbi.nlm.nih.gov/31409387/

2. Cai, Qian, Yang, Hsin-Sheng, Li, Yi-Chen, Zhu, Jiang. 2022. Dissecting the Roles of PDCD4 in Breast Cancer. In Frontiers in oncology, 12, 855807. doi:10.3389/fonc.2022.855807. https://pubmed.ncbi.nlm.nih.gov/35795053/

3. Lu, Kaikai, He, Lei, Guo, Zizhen, Wu, Yue, Li, Dongmin. 2024. PDCD4 deficiency in hepatocytes exacerbates nonalcoholic steatohepatitis through enhanced MHC class II transactivator expression. In Metabolism: clinical and experimental, 161, 156036. doi:10.1016/j.metabol.2024.156036. https://pubmed.ncbi.nlm.nih.gov/39342987/

4. Long, Jiali, Yin, Yuting, Guo, Haina, Zeng, Chao, Zhu, Wei. 2018. The mechanisms and clinical significance of PDCD4 in colorectal cancer. In Gene, 680, 59-64. doi:10.1016/j.gene.2018.09.034. https://pubmed.ncbi.nlm.nih.gov/30243936/

5. Zhang, Jie, Qin, Mengzhen, Kao, Chunyu, Qin, Yingying, Ding, Lingling. 2023. PDCD4 deficiency improved 4-vinylcyclohexene dioxide-induced mouse premature ovarian insufficiency. In Reproductive biomedicine online, 48, 103685. doi:10.1016/j.rbmo.2023.103685. https://pubmed.ncbi.nlm.nih.gov/38324980/

6. Yu, Li, Yang, Yuchun, Wang, Jiao, Zhu, Yu, Wulasihan, Muhuyati. 2024. PDCD4 promotes inflammation/fibrosis by activating the PPAR‑γ/NF‑κB pathway in mouse atrial myocytes. In Molecular medicine reports, 30, . doi:10.3892/mmr.2024.13333. https://pubmed.ncbi.nlm.nih.gov/39301631/